Time for a reassessment of the treatment of hypothyroidism

Abstract

Background In the treatment for hypothyroidism, a historically symptom-orientated approach has given way to reliance on a single biochemical parameter, thyroid stimulating hormone (TSH). Main body The historical developments and motivation leading to that decision and its potential implications are explored from pathophysiological, clinical and statistical viewpoints. An increasing frequency of hypothyroid-like complaints is noted in patients in the wake of this directional shift, together with relaxation of treatment targets. Recent prospective and retrospective studies suggested a changing pattern in patient complaints associated with recent guideline-led low-dose policies. A resulting dramatic rise has ensued in patients, expressing in various ways dissatisfaction with the standard treatment. Contributing factors may include raised problem awareness, overlap of thyroid-related complaints with numerous non-specific symptoms, and apparent deficiencies in the diagnostic process itself. Assuming that maintaining TSH anywhere within its broad reference limits may achieve a satisfactory outcome is challenged. The interrelationship between TSH, free thyroxine (FT4) and free triiodothyronine (FT3) is patient specific and highly individual. Population-based statistical analysis is therefore subject to amalgamation problems (Simpson’s paradox, collider stratification bias). This invalidates group-averaged and range-bound approaches, rather demanding a subject-related statistical approach. Randomised clinical trial (RCT) outcomes may be equally distorted by intra-class clustering. Analytical distinction between an averaged versus typical outcome becomes clinically relevant, because doctors and patients are more interested in the latter. It follows that population-based diagnostic cut-offs for TSH may not be an appropriate treatment target. Studies relating TSH and thyroid hormone concentrations to adverse effects such as osteoporosis and atrial fibrillation invite similar caveats, as measuring TSH within the euthyroid range cannot substitute for FT4 and FT3 concentrations in the risk assessment. Direct markers of thyroid tissue effects and thyroid-specific quality of life instruments are required, but need methodological improvement. Conclusion It appears that we are witnessing a consequential historic shift in the treatment of thyroid disease, driven by over-reliance on a single laboratory parameter TSH. The focus on biochemistry rather than patient symptom relief should be re-assessed. A joint consideration together with a more personalized approach may be required to address the recent surge in patient complaint rates.

The Two Faces of Janus: Why Thyrotropin as a Cardiovascular Risk Factor May Be an Ambiguous Target

“…Calculated parameters providing biomarkers for the set point of thyroid homeostasis and peripheral hormone metabolism may provide additional insights, especially in the setting of clinical trials (41). This should avoid ambiguities in the interpretation and provide further direction on potential therapeutic intervention (59).…”

Hypothyreose: Guidelines, neue Erkenntnisse und klinische Praxis

“…Diese Festlegung der Normwerte ist jedoch zuletzt häufig intensiv und kritisch diskutiert worden, v. a. auch durch die Erkenntnis, dass die alleinige TSH-Bestimmung zu wenig Information über die Homöostase und Allostase der Schilddrüsenhormone reflektiert, was auch u. a. dadurch gestützt wird, dass z. B. fT4 besser mit klinischen Parametern korreliert als TSH [5][6][7][8][9][10]. Durch entsprechende mathematische Modellierung lässt sich die individuelle Schilddrüsenfunktion unter Berücksichtigung z.…”

“…Basierend auf den Werten von TSH, fT4 und freiem Trijodthyronin (fT3) lassen sich über mathematische Formeln, welche entsprechende kinetische Eigenschaften berücksichtigen, Parameter berechnen, wie z. B. die SPINA-GT, welche die (primäre) Sekretionsleistung der Schilddrüse anzeigt, oder der Jostel-TSH-Index, der die zentrale (hypophysäre) Stimulation der Schilddrüse reflektiert [5][6][7][8][9]. Auch wenn sich diese Parameter in der Klinik noch nicht etabliert haben und Gegenstand aktiver Forschung sind, könnten sie uns in Zukunft helfen, eine individuellere und bessere Diagnostik und Therapie von Schilddrüsenfunktionsstörungen zu etablieren, die über unser simples, lineares und TSH-zentriertes Denken hinausgeht.…”

Individualised requirements for optimum treatment of hypothyroidism: complex needs, limited options

“…It has become increasingly apparent that a historic experiment using an ill-founded ‘one size fits all’ approach and a simplistic TSH-centred method for defining a prevalent disease such as hypothyroidism has failed 98. TSH measurement cannot be dissociated from either the clinical presentation of the patient, the specific underlying condition it applies to, its intricate interlocking pattern with thyroid hormones, or its personal trait-like nonergodicity (Figure 1).…”

“…Although LT4 has been the guideline-endorsed standard treatment for hypothyroidism since its introduction in the 1970s, the universality of this choice has been disputed 99,100. Critics have argued that the transition from the earlier use of thyroid extracts, which still remain a popular choice amongst patients, to LT4 was not supported by strict evidence-based criteria at that time, and a few rigorous comparative studies have only emerged recently 98,101.…”